[Effects of CS-866, an angiotensin II receptor antagonist, in 5/6 nephrectomized spontaneously hypertensive rats]

To assess the chronic antihypertensive and renal protective effects of the specific angiotensin II receptor antagonist, CS-866, in the remnant kidney model of chronic renal failure, we administered it alone or in combination with temocapril, an angiotensin converting enzyme inhibitor, to 5/6 nephrectomized spontaneously hypertensive rats (SHR) for 8 weeks. At the age of 10 weeks, 5/6 nephrectomized SHR were allocated to receive two doses of CS-866 (CS-3; 3 mg/kg/day, or CS-10; 10 mg/kg/day), temocapril (TEM; 10 mg/kg/day), a combination of CS-866 (3 mg/kg/day) and temocapril (10 mg/kg/day) or the vehicle alone via oral gavage for 8 weeks. Systolic blood pressure (SBP) and urinary protein excretion (UprotV) were measured every two weeks. At the age of 18 weeks, the rats were decapitated and the blood, remnant kidney, aorta and heart were collected and used for biochemical measurements and histopathological studies. There was no significant difference in body weight among the groups during the study. All drug treatments significantly reduced SBP, UprotV, glomerular sclerosis index (GSI), relative interstitial volume (RIV) and the heart weight to body weight ratio. The hypotensive effects were in the order of combination therapy > CS-10 = TEM > CS-3. For correlational analysis, we used values for SBP and UprotV derived from the average of values in rats over the age of 12 weeks through 18 weeks. UprotV, GSI and RIV were found to be highly correlated with SBP among the individual rats pooled from all groups (r = 0.511, r = 0.754, r = 0.817, respectively) and the correlation was maintained among the group means (r = 0.945, r = 0.989, r = 0.918, respectively). Furthermore, the heart weight to body weight ratio was found to be highly correlated with SBP among the individual rats pooled from all groups (r = 0.923) and the correlation was maintained among the group means (r = 0.996). We conclude that organ protective effects of CS-866, TEM, or combination therapy are closely related to the magnitude of their antihypertensive effects.